Distribution of Estrogen Receptor-Immunoreactive Cells in Monkey Hypothalamus: Relationship to Neurones Containing Luteinizing Hormone-Releasing Hormone and Tyrosine Hydroxylase

Abstract

The precise sites and mechanisms by which gonadal steroids influence the activity of neuroendocrine cells controlling pituitary hormone secretion are poorly understood. The present study has determined the distribution of estrogen receptor (ER)-immunoreactive cells in the monkey hypothalamus and examined whether ERs are expressed by luteinising hormone-releasing hormone (LHRH)-and/or dopamine-containing neurones. The distribution of ER-immunoreactive cells was determined in ovariectomised (n = 2) and estrogen plus progesterone-treated (n = 2) cynomolgus macaques and in a single ovariectomised African green monkey. Large numbers of cells immunoreactive for the ER were detected in the preoptic area, bed nucleus of the stria terminalis, periventricular area and ventromedial and arcuate nuclei of all monkeys irrespective of the steroid status. Smaller numbers of ER-immunoreactive cells were found in the paraventricular, but not supraoptic nucleus. Double-labeling experiments in sections from all 5 monkeys revealed that none of the 432 LHRH neurons examined possessed detectable ER immunoreactivity. Neurones stained for tyrosine hydroxylase (TH) were identified in the A11, A12, and A14 cell groups and, although Al 1 and A12 neurones were intermingled amongst and found adjacent to ER-immunoreactive cells, none of the 1,652 TH-immunoreactive cells examined contained ER immunoreactivity. These results show that ER-immunoreactive cells in the monkey hypothalamus are distributed in a manner similar to that observed in other mammalian species although not all brain regions reported to contain progesterone receptors (PRs) in these species of monkey were found to express ERs. The double-labelling experiments provide further evidence that LHRH neurones do not possess ERs and indicate that, as in other species, estrogen influences on primate LHRH neurones are indirect and/or non-genomic in nature. Unlike the rat and sheep, no evidence was found for ER immunoreactivity in hypothalamic dopaminergic neurones of the monkey. The discrepancy in ER and reported PR receptor localisation within specific hypothalamic nuclei as well as in dopaminergic neurones raises the possibility that not all PR-containing cells may express ERs in the primate hypothalamus.

Progesterone Can Block Transmission of the Estradiol-Induced Signal for Luteinizing Hormone Surge Generation during a Specific Period of Time Immediately after Activation of the Gonadotropin-Releasing Hormone Surge-Generating System

“…In conjunction with the observation that GnRH neurons do not possess classical steroid receptors (11)(12)(13)(14)(15), these findings suggest that the surge-inducing estradiol signal is transmitted indirectly to the GnRH neurosecretory system through a series of one or more interneurons. Progesterone is known to block the ability of estradiol to stimulate a preovulatory GnRH/LH surge (10), but whether progesterone blocks activation of the system by estradiol, the activity of the interneurons involved in signal transmission or GnRH secretion itself, remains unknown.…”

“…Eight ewes were exposed to four treatments, over successive artificial estrous cycles. Positive and negative controls were similar to those described in Study 1, except the duration of the stimulatory estradiol signal was reduced to 8 h. The two experimental groups consisted of an EARLY P (progesterone) treatment, in which progesterone was given from hours 8 -13 after estradiol insertion (immediately after estradiol removal), and a LATE P treatment, in which progesterone was given from hours [13][14][15][16][17][18] (immediately before LH surge secretion). As expected, LH surges were stimulated and blocked, in response to the positive and negative controls, respectively.…”

“…Immunocytochemical studies in sheep, as well as a number of other species, have been unable to locate classical steroid receptors within GnRH neurons (11)(12)(13)(14)(15). This has led to the proposal that steroids influence GnRH secretion indirectly, either via a single steroid-responsive neuronal input, or through a system of interneuronal pathways activated or inhibited by estradiol and progesterone, respectively.…”

Premature elevation in serum insulin-like growth factor-I advances first ovulation in rhesus monkeys

“…In adult animals, gonadal steroids inhibit LH secretion by decreasing the activity of neurons in the mediobasal hypothalamus (O'Bryne et al 1993), resulting in a decrease in LHRH biosynthesis (Toranzo et al 1989) and release (Karsch et al 1987). Since LHRH neurons do not contain estrogen receptors, these inhibitory effects of estradiol on LHRH biosynthesis and release are complex and probably involve an interneuronal pathway (Herbison et al 1995, Sullivan et al 1995, possibly the activation of the inhibitory neurotransmitter -aminobutyric acid (GABA) in discrete hypothalamic neurons (Herbison et al 1991, McRee & Meyer 1993. The expression of estrogen receptors on GABAergic and glutamate neurons increases developmentally in female monkeys (Thind & Goldsmith 1997).…”

An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane-3β,17β-diol

“…In the brain, gonadotropin-releasing hormone (GnRH) is the primary upstream regulator of reproductive function and it is well accepted that testosterone and estradiol exert tight control over the negative feedback pathways that regulate GnRH synthesis and release. However, since initial efforts aimed at detecting AR and ER in GnRH neurons failed (Huang andHarlan, 1993, Shivers et al, 1983),, many investigators concluded that the effects of steroid hormones on GnRH were mediated indirectly (Herbison et al, 1995;Herbison and Theodosis, 1992;Lehman and Karsch, 1993). However, the identification of ERbeta resurrected this longstanding hypothesis, as several laboratories subsequently showed the co-expression of GnRH and ERβ (Hrabovszky et al, 2000;Hrabovszky et al, 2001;Kallo et al, 2001;Skynner et al, 1999).…”